A small molecule K-3 promotes PDX1 expression and potentiates the differentiation of pluripotent stem cells into insulin-producing pancreatic β cells.

Abstract

Insulin-producing pancreatic β-like cells derived from human pluripotent stem cells (PSCs) are anticipated as a novel cell source for cell replacement therapy for patients with diabetes. Here, we describe the identification of small molecule compounds that promote the differentiation of the PSCs into insulin-producing cells by high throughput screening with a chemical library composed of 55 000 compounds. The initial hit compound K-1 and one derivative K-3 increased the proportion of PSC-derived insulin-positive endocrine cells and their glucose-stimulated insulin secretory (GSIS) functions. K-3 preferentially acts on stage 3 pancreatic progenitor cells and increases the population expressing high levels of PDX1. As a result, the ratios of the PSC-derived PDX1/NKX6.1 double-positive endocrine progenitor and INS/NKX6.1 double-positive mono-hormonal endocrine cells were increased. K-3 enhances the expression of functional pancreatic β cell markers and affects biological processes concerning organ development. K-3 also increased the yield of endocrine cells at the end of stage 5. The novel compound is a beneficial new tool for efficiently generating PSC-derived insulin-producing cells with high functionality and differentiation efficiency.